4.1. Therapeutic indications

Lytgobi monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy.

4.2. Posology and method of administration

Lytgobi therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with biliary tract cancer.

Presence of FGFR2 gene fusions or rearrangements should be confirmed by an appropriate diagnostic test prior to initiation of Lytgobi therapy.

Posology

The recommended starting dose is 20 mg futibatinib taken orally once daily.

If a dose of futibatinib is missed by more than 12 hours or vomiting occurs after taking a dose, an additional dose should not be taken, and treatment should be resumed with the next scheduled dose.

Treatment should be continued until disease progression or unacceptable toxicity.

In all patients, dietary restrictions that limit phosphate intake are recommended as part of hyperphosphatemia management. A phosphate-lowering therapy should be initiated when serum phosphate level is ≥ 5.5 mg/dL. If the serum phosphate level is > 7 mg/dL, the dose of futibatinib should be modified based on the duration and severity of hyperphosphatemia (see Table 2). Prolonged hyperphosphatemia can cause soft tissue mineralization, including cutaneous calcification, vascular calcification, and myocardial calcification (see section 4.4).

If Lytgobi treatment is stopped or serum phosphate level falls below normal range, phosphate-lowering therapy and diet should be discontinued. Severe hypophosphatemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and hemolytic anemia.

Dose adjustment due to drug interaction

Concomitant use of futibatinib with strong CYP3A inhibitors

Co-administration of futibatinib with strong CYP3A4 inhibitors, such as itraconazole, should be avoided (see sections 4.4 and 4.5). If this is not possible, based on careful monitoring of tolerability, a futibatinib dose reduction to the next lower level should be considered.

Concomitant use of futibatinib with strong or moderate CYP3A inducers

Co-administration of futibatinib with strong or moderate CYP3A4 inducers, such as rifampicin, should be avoided (see sections 4.4 and 4.5). If this is not possible, gradually increasing the futibatinib dose based on careful monitoring of tolerability should be considered.

Management of toxicities

Dose modifications or interruption of dosing should be considered for the management of toxicities. The recommended dose reduction levels are provided in Table 1.

Table 1: Recommended futibatinib dose reduction levels

Dose

Dose reduction levels

20 mg taken orally once daily

First

Second

16 mg taken orally once daily

12 mg taken orally once daily

Treatment should be permanently discontinued if patient is unable to tolerate 12 mg futibatinib once daily.

Dose modifications for hyperphosphatemia are provided in Table 2.

Table 2: Dose modifications for hyperphosphatemia

Adverse reaction

Futibatinib dose modification

Serum phosphate

≥5.5 mg/dL - ≤ 7 mg/dL

• Initiate phosphate lowering therapy and monitor serum phosphate weekly

• Futibatinib should be continued at current dose

Serum phosphate

>7 mg/dL - ≤ 10 mg/dL

• Initiate/intensify phosphate lowering therapy and monitor serum phosphate weekly AND

• Dose reduce futibatinib to next lower dose

– If the serum phosphate resolves to ≤7.0 mg/dL within 2 weeks after dose reduction, continue at this reduced dose

– If serum phosphate is not ≤ 7.0 mg/dL within 2 weeks, further reduce futibatinib to the next lower dose

– If serum phosphate is not ≤ 7.0 mg/dL within 2 weeks after the second dose reduction, withhold futibatinib until serum phosphate is ≤ 7.0 mg/dL and resume at the dose prior to suspending

Serum phosphate

>10 mg/dL

• Initiate/intensify phosphate lowering therapy and monitor serum phosphate weekly AND

• Suspend futibatinib until phosphate is ≤ 7.0 mg/dL and resume futibatinib at the next lower dose

• Permanently discontinue futibatinib if serum phosphate is not ≤ 7.0 mg/dL within 2 weeks following 2 dose reductions

Dose modifications for serous retinal detachment are provided in Table 3.

Table 3: Dose modifications for serous retinal detachment

Adverse reaction

Futibatinib dose modification

Asymptomatic

• Continue futibatinib at current dose. Monitoring should be performed as described in section 4.4.

Moderate decrease in visual acuity (best corrected visual acuity 20/40 or better or ≤ 3 lines of decreased vision from baseline); limiting instrumental activities of daily living

• Withhold futibatinib. If improved on subsequent examination, futibatinib should be resumed at the next lower dose level.

• If symptoms recur, persist or examination does not improve, permanent discontinuation of futibatinib should be considered based on clinical status.

Marked decrease in visual acuity (best corrected visual acuity worse than 20/40 or >3 lines decreased vision from baseline up to 20/200); limiting activities of daily living

• Withhold futibatinib until resolution. If improved on subsequent examination, futibatinib may be resumed at 2 dose levels lower.

• If symptoms recur, persist or examination does not improve, permanent discontinuation of futibatinib should be considered based on clinical status.

Visual acuity worse than 20/200 in affected eye; limiting activities of daily living

• Permanent discontinuation of futibatinib should be considered based on clinical status.

Dose modifications for other adverse reactions are provided in Table 4.

Table 4: Dose modifications for other adverse reactions

Other Adverse Reactions

Grade 3a

• Withhold futibatinib until toxicity resolves to Grade 1 or baseline, then resume futibatinib

– for hematological toxicities resolving within 1 week, at the dose prior to suspending.

– for other adverse reactions, at next lower dose.

Grade 4a

Permanently discontinue futibatinib

a Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03).

Special populations

Elderly

No specific dose adjustment is required for elderly patients (≥ 65 years) (see section 5.1).

Renal impairment

Dose adjustment is not required for patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). There are no data in patients with severe renal impairment (CLcr < 30 mL/min) or for patients with end-stage renal disease receiving intermittent haemodialysis and therefore no dosing recommendation can be made (see section 5.2).

Hepatic impairment

No dose adjustment is required when administering futibatinib to patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment. However, there is no safety data in patients with severe hepatic impairment. (see section 5.2).

Paediatric population

The safety and efficacy of futibatinib in children less than 18 years of age have not been established. No data are available.

Method of administration

Lytgobi is for oral use. The tablets should be taken with or without food at about the same time each day. The tablets should be swallowed whole to ensure that the full dose is administered.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Hyperphosphatemia

Hyperphosphatemia is a pharmacodynamic effect expected with futibatinib administration (see section 5.1). Prolonged hyperphosphatemia may cause soft tissue mineralization, including cutaneous calcification, vascular calcification, and myocardial calcification, anaemia, hyperparathyroidism, and hypocalcemia that may cause muscle cramps, QT interval prolongation, and arrythmias (see section 4.2).

Recommendations for management of hyperphosphatemia include dietary phosphate restriction, administration of phosphate-lowering therapy, and dose modification when required (see section 4.2).

Phosphate-lowering therapy was used by 83.4 % of patients during treatment with futibatinib (see section 4.8).

Serous retinal detachment

Futibatinib can cause serous retinal detachment, which may present with symptoms such as blurred vision, visual floaters, or photopsia (see section 4.8). This can moderately influence the ability to drive and use machines (see section 4.7).

Ophthalmological examination should be performed prior to initiation of therapy, 6 weeks thereafter, and urgently at any time for visual symptoms. For serous retinal detachment reactions, the dose modification guidelines should be followed (see section 4.2).

During the conduct of the clinical study, there was no routine monitoring, including optical coherence tomography (OCT), to detect asymptomatic serous retinal detachment; therefore, the incidence of asymptomatic serous retinal detachment with futibatinib is unknown.

Careful consideration should be taken with patients that have clinically significant medical eye disorders, such as retinal disorders, including but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, and previous retinal detachment.

Dry eye

Futibatinib can cause dry eye (see section 4.8). Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.

Embryo-foetal toxicity

Based on the mechanism of action and findings in an animal study (see section 5.3), futibatinib can cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus. An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Lytgobi and for 1 week following completion of therapy, barrier methods should be applied as a second form of contraception to avoid pregnancy (see section 4.6). A pregnancy test should be performed before treatment initiation to exclude pregnancy.

Combination with strong CYP3A inhibitors

Concomitant use of strong CYP3A inhibitors should be avoided because it may increase futibatinib plasma concentration (see sections 4.2 and 4.5).

Combination with strong or moderate CYP3A inducers

Concomitant use of strong or moderate CYP3A inducers should be avoided because it may decrease futibatinib plasma concentration (see sections 4.2 and 4.5).

Lactose

Lytgobi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

Lytgobi contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on futibatinib

CYP3A inhibitors

Co-administration of multiple doses of 200 mg itraconazole, a strong CYP3A inhibitor, increased futibatinib Cmax by 51% and AUC by 41% following a single oral dose of 20 mg futibatinib. Therefore, the concomitant use of strong CYP3A inhibitors (e.g. clarithromycin, itraconazole) may increase futibatinib plasma concentration and should be avoided. If this is not possible, a reduction in the futibatinib dose to the next lower dose level based on tolerability observed should be considered (see sections 4.2 and 4.4).

CYP3A inducers

Co-administration of multiple doses of 600 mg rifampin, a strong CYP3A inducer, decreased futibatinib Cmax by 53% and AUC by 64% following a single oral dose of 20 mg futibatinib. Therefore, the concomitant use of strong or moderate CYP3A inducers (e.g. carbamazepine, phenytoin, phenobarbital, efavirenz, rifampin) may decrease futibatinib plasma concentration and should be avoided. If this is not possible, gradually increasing the futibatinib dose based on careful monitoring of tolerability should be considered (see sections 4.2 and 4.4).

P-gp inhibitors

Co-administration of multiple doses of 200 mg quinidine, a P-gp inhibitor, increased futibatinib Cmax by 8% and AUCinf by 17% following a single oral dose of 20 mg futibatinib. Therefore, co- administration of P-gp inhibitors is not likely to have a clinically relevant effect on futibatinib exposure.

Proton pump inhibitors

Futibatinib geometric mean ratios for Cmax and AUC were 108% and 105%, respectively, when co-administered in healthy subjects with lansoprazole (a proton pump inhibitor) relative to futibatinib alone. Therefore, co-administration of proton pump inhibitors is not likely to have a clinically relevant effect on futibatinib exposure.

Effects of futibatinib on other medicinal products

Effect of futibatinib on CYP3A substrate

Midazolam (a CYP3A sensitive substrate) geometric mean ratios for Cmax and AUC were 95% and 91%, respectively, when co-administered in healthy subjects with futibatinib relative to midazolam alone. Therefore, co-administration of futibatinib is not likely to have a clinically relevant effect on the exposure of CYP3A substrates.

Effect of futibatinib on P-gp substrates

Digoxin (a sensitive P-gp substrate) geometric mean ratios for Cmax and AUCinf were 95% and 100%, respectively, when co-administered in healthy subjects with futibatinib relative to digoxin alone. Therefore, co-administration of futibatinib is not likely to have a clinically relevant effect on the exposure of P-gp substrates.

Effect of futibatinib on BCRP substrates

Rosuvastatin (a sensitive BCRP substrate) geometric mean ratios for Cmax and AUCinf were 110% and 113%, respectively, when co-administered in healthy subjects with futibatinib relative to rosuvastatin alone. Therefore, co-administration of futibatinib is not likely to have a clinically relevant effect on the exposure of BCRP substrates.

Effect of futibatinib on CYP1A2 substrates

In vitro studies indicate that futibatinib has the potential to induce CYP1A2. Co-administration of futibatinib with CYP1A2 sensitive substrates (e.g, olanzapine, theophylline) may decrease their exposure and therefore may affect their activity.

Hormonal contraceptives

It is currently unknown whether futibatinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method during Lytgobi treatment and for at least 1 week after the last dose (see section 4.6).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Lytgobi and for 1 week following completion of therapy. Since the effect of futibatinib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy.

Pregnancy

There are no available data from the use of futibatinib in pregnant women. Studies in animals have shown embryo-foetal toxicity (see section 5.3). Lytgobi should not be used during pregnancy unless the potential benefit for the women justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether futibatinib or its metabolites are excreted in human milk. A risk to the breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lytgobi and for 1 week after the last dose.

Fertility

There are no data on the effect of futibatinib on human fertility. Animal fertility studies have not been conducted with futibatinib (see section 5.3). Based on the pharmacology of futibatinib, impairment of male and female fertility cannot be excluded.

4.7. Effects on ability to drive and use machines

Futibatinib has moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or operating machines in case they experience fatigue or visual disturbances during the treatment with Lytgobi (see section 4.4).

4.8. Undesirable effects

Summary of the safety profile

The most common (≥20%) adverse reactions were hyperphosphatemia (89.7%), nail disorders (44.1%), constipation (37.2%), alopecia (35.2%), diarrhoea (33.8%), dry mouth (31.0%), fatigue (31.0%), nausea (28.3%), dry skin (27.6%), increased AST (26.9%), abdominal pain (24.8%), stomatitis (24.8%), vomiting (23.4%), palmar-plantar erythrodysaesthesia syndrome (22.8%), arthralgia (21.4%), and decreased appetite (20.0%).

The most common serious adverse reactions were intestinal obstruction (1.4%) and migraine (1.4%).

Permanent discontinuation due to adverse reactions was reported in 7.6% of patients; the most common adverse reaction led to dose discontinuation was stomatitis (1.4%), all other adverse reactions were single occurrence.

Tabulated list of adverse reactions

Table 5 summarises the adverse reactions occurring in 145 patients treated in the indicated population of Study TAS‑120-101. Median duration of exposure of futibatinib was 8.87 months (min: 0.5, max: 31.7). Adverse reactions are listed according to MedDRA system organ class (SOC). Frequency categories are very common (≥ 1/10) and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5: Adverse reactions observed in the indicated population in TAS-120-101 study (N=145) – frequency reported by incidence of treatment emergent events

System organ class

Frequency

Adverse reactions

Metabolism and nutrition disorders

Very common

Hyperphosphatemia

Decreased appetite

Hyponatraemia

Hypophosphataemia

Nervous system disorders

Very common

Dysgeusia

Common

Migraine

Eye disorders

Very common

Dry eye

Common

Serous retinal detachmenta

Gastrointestinal disorders

Very common

Stomatitis

Diarrhoea

Nausea

Constipation

Dry mouth

Vomiting

Abdominal pain

Common

Intestinal obstruction

Skin and subcutaneous tissue disorders

Very common

Palmar-plantar erythrodysaesthesia syndrome

Nail disordersb

Dry skin

Alopecia

Musculoskeletal and connective tissue disorders

Very common

Myalgia

Arthralgia

General disorders and administration site conditions

Very common

Fatigue

Investigations

Very common

Liver transaminases increased

a Includes serous retinal detachment, detachment of retinal pigment epithelium, subretinal fluid, chorioretinopathy, macular oedema, and maculopathy. See below “Serous retinal detachment”.

b Includes nail toxicity, nail bed tenderness, nail disorder, nail discolouration, nail dystrophy, nail hypertrophy, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis and paronychia.

Description of selected adverse reactions

Hyperphosphatemia

Hyperphosphatemia was reported in 89.7% of patients treated with futibatinib and 27.6% patients had Grade 3 events, defined as serum phosphate > 7 mg/dL and ≤ 10 mg/dL irrespective of clinical symptoms. The median time to onset of hyperphosphatemia of any grade was 6.0 days (range: 3.0 to 117.0 days).

None of the reactions were Grade 4 or 5 in severity, serious, or led to discontinuation of futibatinib. Dose interruption occurred in 18.6 % patients and reduction in 17.9 % of patients. Hyperphosphatemia was manageable with dietary phosphate restriction and/or administration of phosphate lowering therapy and /or dose modification.

Recommendations for management of hyperphosphatemia are provided in sections 4.2 and 4.4.

Serous retinal detachment

Serous retinal detachment occurred in 6.2 % of patients treated with futibatinib. Reactions were all Grade 1 or 2 in severity. Dose interruption occurred in 2.1 % of patients and reduction in 2.1 % of patients. None of the reactions led to discontinuation of futibatinib. Serous retinal detachment was generally manageable.

Recommendations for management of serous retinal detachment are provided in sections 4.2 and 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no information on overdose of futibatinib.